Alzheimer's disease (AD), the most common form of dementia, is a leading cause of death in the United States and costs the nation more than $200 billion/year. Unfortunately, there are currently no effective treatments to slow or halt cognitive decline in AD patients, highlighting the need for new therapeutic targets and treatment approaches. Stressful life experiences and chronic stress are risk factors for AD. Indeed, both unpredictable stress and glucocorticoids (GCs; the major stress hormones) trigger AD pathomechanisms in rodent models. These include amyloid precursor protein (APP) misprocessing, leading to toxic amyloid-beta overproduction, and Tau hyperphosphorylation, leading to synaptic mislocalization of Tau and downstream synaptic/neuronal loss. However, very little is known about the molecular and cellular mechanisms through which chronic stress/GCs promote AD pathogenesis. Such information will be essential for developing therapeutic strategies to treat or prevent AD. To elucidate these mechanisms, we have focused on the Rab family of GTPases, key regulators of protein trafficking. In particular, we have identified Rab35 as a GTPase whose activation suppresses GC-induced APP and Tau pathology in hippocampal neurons. Remarkably, we also find that prolonged GC exposure significantly and specifically decreases Rab35 levels in rodent hippocampus, suggesting that downregulation of Rab35 may precipitate stress/GC-induced AD pathogenesis. Our findings have led us to hypothesize that Rab35 is a suppressor of stress-induced AD pathomechanisms, and may represent a novel therapeutic target for AD treatment. In the current proposal, we will test this hypothesis while illuminating Rab35's role in APP and Tau trafficking. First, we will investigate the mechanisms through which APP processing is regulated by Rab35 and GCs. We will determine how Rab35 prevents amyloidogenic APP processing, and whether Rab35's protective role extends to mutant forms of APP that cause familial AD. We will also investigate the molecular pathway through which GCs induce APP misprocessing. Second, we will define Rab35's role in counteracting GC-induced Tau hyperphosphorylation and missorting. Here, we will focus on Rab35's ability to stimulate Tau degradation, and assess whether this degradative role extends to mutant forms of Tau linked to human tauopathy. Third, we will investigate Rab35's link to aging and AD pathology in human brain tissue, and its therapeutic potential in stress/GC rodent models. Specifically, we will test whether AAV-mediated expression of Rab35 in the rodent hippocampus can ameliorate pathological and behavioral features of AD in stressed and GC-treated animals. These studies will provide a mechanistic understanding of Rab35-linked regulation of APP and Tau pathology, and simultaneously evaluate Rab35 as a novel therapeutic target for treating AD.